m- and p-Substituted-.alpha.-phenylpropionic acids or phenylacetic acids, their salts, esters etc. are presently being marketed as anti-inflammatory agents or peripheral analgesics. Among these agents are ibuprofen, (.+-.) .alpha.-methyl-4-(2-methylpropyl)benzeneacetic acid; carprofen, (.+-.) .alpha.-6-chloro-.alpha.-methylcarbazole-2-acetic acid; cicloprofen, .alpha.-methylfluorene-2-acetic acid; fenoprofen, dl-.alpha.-methyl-3-phenoxybenzeneacetic acid; indoprofen, .alpha.-methyl-4-(1,3-dihydro-1-oxo-2H-isoindoyl-2-yl)benzeneacetic acid; ketoprofen, .alpha.-methyl-3-benzoylbenzeneacetic acid; naproxyn, (+) .alpha.-methyl-6-methoxy-2-naphthaleneacetic acid; pirprofen, dl-3-chloro-4-(2,5-dihydro-1H-pyrrolo-1-yl)-.alpha.-methylbenzeneacetic acid; suprofen, dl-.alpha.-methyl-4-(2-thienylcarbonyl)benzeneacetic acid and benzoxoprofen, dl-.alpha.-methyl-2-(p-chlorophenyl)benzoxazoleacetic acid. A common method of preparing these compounds is to start with an acetyl derivative, reduce the carbonyl group to a hydroxyl, replace the hydroxyl with a halogen, react the haloalkyl group with sodium cyanide to yield a propionitrile derivative and then hydrolyze the nitrile group to a carboxylic acid. Alternatively, a benzyl halide can be converted to the corresponding acetonitrile and the active methylene group methylated to yield directly the .alpha.-methyl acetontrile. Several of these methods are set forth in U.S. Pat. No. 3,600,437 which covers fenoprofen.
In general, the most desirable route for preparing any one of the above "profen" antiinflammatory agents depends primarily upon the availability of the starting material. For example, starting materials for the synthesis of fenoprofen can be selected from among m-bromoacetophenone, m-hydroxyacetophenone, m-bromophenylacetonitrile etc. In addition, certain of the side chain functional groups; i.e. hydroxy or carbonyl, affect the course of a reaction to replace the m-bromo or m-hydroxy group in the phenyl ring with a phenoxy or other group. Alternative methods for the preparation of any of the "profen" anti-inflammatory agents and particularly of fenoprofen are clearly desirable.
One of the synthetic routes available for the manufacture of benoxaprofen is set forth in U.S. Pat. No. 3,912,748 (also U.S. Pat. No. Re 29,608) both based on a British provisional application No. 23409/72 filed May 18, 1972. This procedure involves nitration of p-ethylphenol followed by acylation of the phenolic group by p-chlorobenzoyl chloride and cyclization of the acylated phenol. The resulting compound, 2-(p-chlorophenyl)-5-ethylbenzoxazole, is brominated by a free radical mechanism on the alpha carbon of the ethyl side chain to yield .alpha.-methyl-2-(p-chlorophenyl)-5-benzoxazolylmethylbromide a compound also used in the standard synthesis of benoxaprofen and a compound which can be readily converted to the corresponding nitrile and thence to the acid followed by cyclization. Free radical bromination steps are clearly not useful for the synthesis of all "profen" anti-inflammatory agents since there may be other groups in the molecule which could also react with bromine by a free radical mechanism. For example, in a comparable synthesis of ibuprofen, the compound to be brominated would be p-isobutylethylbenzene in which either alkyl group would react with a free bromine radical.
A recent West German OLS No. 2,707,232 of Aug. 24, 1978, filed Feb. 19, 1977, discloses and claims a method for preparing m-phenoxybenzyl bromides or chlorides in which the carbon to be halogenated can also be substituted by another halogen, or an alkyl, aryl, C.sub.1 -C.sub.4 haloalkyl, alkoxycarbonyl, cyano or nitro group. A free radical bromination is employed.
It is an object of this invention to provide a process for the preparation of fenoprofen in good yield and of excellent purity starting with m-ethylphenol. It is a further object of this invention to provide a method of brominating m-ethyldiphenyl ether in high yield.